Hematopoietic cell transplantation (HCT) remains the only curative treatment for sickle cell disease (SCD), which is characterized by substantial morbidity, functional impairment, poor quality of life and premature mortality. The results of HCT for SCD from HLA-identical sibling donors are excellent with over 94% overall (OS) and 91% event-free survival (EFS). The emergence of HCT from alternate donors, and autologous genetically modified hematopoietic progenitor cells has the potential to dramatically increase the applicability of HCT for SCD. Clinical trials and research registries collect HCT related outcomes such as OS and EFS in the short and intermediate term but do not capture long- term clinical or patient reported outcomes (PROs), or biospecimens. They also do not compare outcomes in those who have undergone HCT to untransplanted individuals with SCD or healthy controls with similar genetic predilection and environmental exposures. This limits our ability to study late complications of HCT such as gonadal dysfunction, secondary neoplasms, impairment of health-related quality of Life (HR-QoL), immune dysregulation, and cardiovascular disease (CVD) or draw conclusions about the long-term benefit of HCT in patients with SCD. In contrast to patients with malignancies, individuals with SCD undergoing HCT may have different risks post-HCT. On the on the one hand, they have not been exposed to anthracyclines, high-dose radiation, or high rates of chronic graft versus host disease (cGVHD); on the other hand they are subject to unique multi-organ pathology related to prior chronic vaso-occlusion, hemolysis, inflammation, iron overload, impaired immune function, organ damage and poor HRQoL. There is a paucity of data about late effects and long-term outcomes of HCT for chronic, multi-system, non-malignant diseases such as SCD as compared to patients with leukemia. Lack of data on long-term benefit of HCT compared to standard of care may contribute to decisional dilemma and the comparative under-utilization of HCT as a curative treatment. The increasing application of HCT for SCD with the use of alternate donors, alternate GVHD prophylaxis and more recently, autologous HCT with gene addition and gene editing underscore the urgent imperative for an evidence base for long-term clinical and PROs of HCT in keeping with the vision of Cure sickle cell initiative (CureSCi) to accelerate the development of treatments aimed at a genetic-based cure for SCD. In collaboration with the Center for International Bone Marrow Transplant Research (CIBMTR), we have assembled a North American consortium, pilot-tested, and refined infrastructure, and generated preliminary data to establish the feasibility of recruitment, retention, and of completing study procedures for a large cohort of survivors of HCT for SCD, untransplanted SCD controls, matched for age, gender, SCD genotype, as well as healthy siblings, in a prospective registry to address critical knowledge gaps.